A. Field of the Invention
The invention relates to compositions and methods for enhancing nitric oxide production in the oral cavity and more specifically to compositions and methods for enhancing nitric oxide production that comprise probiotics.
B. Description of Related Art
The human gastrointestinal tract represents a major habitat for bacterial colonization. For example, the microbiota of the lower intestinal tract is widely recognized to play a symbiotic role in maintaining a healthy host physiology by participating in nutrient acquisition and bile acid recycling, among other activities. Another region where microbiota can be found is in the oral cavity.
While, the role of upper gastrointestinal tract microbiota in disease is well studied, specific contributions to host health are not well defined. One potential symbiotic relationship between oral bacteria and humans is via the entero-salivary nitrate-nitrite-nitric oxide pathway, which can positively affect nitric oxide (NO) production and homeostasis. (Lundberg, Weitzberg et al. 2004; Lundberg, Weitzberg et al. 2008).
The gaseous free radical NO, which is endogenously produced in vascular endothelial cells, neurons and immune cells, plays a critical role in various physiological processes, including vascular homeostasis, neurotransmission, and host defense mechanisms, respectively. Continuous availability of NO is essential for cardiovascular system integrity. In the circulation, NO is an important regulator of vascular tone and blood pressure, and inhibits oxidative stress, platelet aggregation, and leukocyte adhesion (Moncada, Palmer et al. 1991). NO insufficiency is strongly correlated with cardiovascular risk factors (Kleinbongard, Dejam et al. 2006), is causal for endothelial dysfunction, and serves as a profound predictive factor for future atherosclerotic disease progression (Schachinger, Britten et al. 2000; Halcox 2002; Bugiardini, Manfrini et al. 2004; Lerman and Zeiher 2005) and cardiovascular events (Yeboah, Crouse et al. 2007; Yeboah, Folsom et al. 2009). In mammalian systems, NO is generated by NO synthases (NOS) from the amino acid L-arginine and molecular oxygen (Moncada and Higgs 1993). The entero-salivary nitrate-nitrite-NO pathway is a NOS-independent and oxygen-independent pathway to NO formation that is an important alternative pathway to produce bioactive NO, particularly during periods of hypoxia (Lundberg, Weitzberg et al. 2004; Doel, Benjamin et al. 2005; Bryan, Calvert et al. 2008).
Dietary nitrate, obtained primarily from green leafy vegetables and beets, is rapidly absorbed from the upper gastrointestinal tract into the bloodstream, where it mixes with the nitrate formed from the oxidation of endogenous NO produced from mammalian NOS. Up to 25% of this nitrate is actively taken up by the salivary glands and concentrated up to 20-fold, reaching concentrations approaching 10 mM in the saliva (Lundberg and Govoni 2004). Salivary nitrate is metabolized to nitrite via a two-electron reduction, a reaction that mammalian cells are unable to perform, during anaerobic respiration by nitrate reductases produced by facultative and obligate anaerobic commensal oral bacteria (Duncan, Dougall et al. 1995; Lundberg, Weitzberg et al. 2004). Numerous studies have shown that nitrite produced from bacterial nitrate reduction is an important storage pool for NO in blood and tissues when NOS-mediated NO production is insufficient (Bryan, Calvert et al. 2007; Bryan, Calvert et al. 2008; Webb, Patel et al. 2008; Carlstrom, Larsen et al. 2010; Carlstrom, Persson et al. 2011). In various animal models and in humans, dietary nitrate supplementation has shown numerous beneficial effects, including a reduction in blood pressure, protection against ischemia-reperfusion damage, restoration of NO homeostasis with associated cardioprotection, increased vascular regeneration after chronic ischemia, and a reversal of vascular dysfunction in the elderly (Webb, Bond et al. 2004; Petersson, Carlstrom et al. 2009). Some of these benefits were reduced or completely prevented when the oral microbiota were abolished with an antiseptic mouthwash (Petersson, Carlstrom et al. 2009; Hendgen-Cotta, Luedike et al. 2012) Additionally, it was recently shown that in the absence of any dietary modifications, a seven-day period of antiseptic mouthwash treatment to disrupt the oral microbiota reduced both oral and plasma nitrite levels in healthy human volunteers, and was associated with a sustained increase in both systolic and diastolic blood pressure (Kapil, Haydar et al. 2013). There may be a role for oral nitrate-reducing bacteria in making a physiologically relevant contribution to host nitrite and thus NO levels, with measureable physiological effects, and therefore, there is a need for these types of bacteria.